The field of potassium channels has undergone explosive growth in the past several years. Two events have had a major influence on the rapid growth of this area. First, there has been the development of novel electrophysiological methods including whole cell and patch clamp techniques to characterize potassium channel function at the whole cell and single channel level. Second, there has been the recognition that new classes of pharmacological substances can be developed to specifically block or open such channels. For instance, compounds are available that can specifically block the delayed rectifier channel in cardiac muscle (e.g. clofilium and sotalol) and which now serve as prototypes for an important new class of antiarrhythmic agents, the class III agents. More recently, certain drugs which had previously thought to be "nonspecific vasodilators" (e.g., pinacidil and cromakalim) were found to be selective potassium channel openers (PCO's) in vascular smooth muscle.
It is now known that some 30 different potassium channels exist in a variety of biological tissues. Whereas it has long been known that potassium channels play a major role in neuronal excitability, the recent availability of new probes for K channels has helped reveal the complex and critical role these channels play in the basic electrical and mechanical functions of a wide variety of tissues including smooth and cardiac muscle and glands.
PCO's are derived from a wide variety of structural classes. Pinacidil (N"-cyano-N-4-pyridyl-N'-1,2,2-trimethylpropylguanidine) was derived from a series of alkylpyridylthioureas, which had been demonstrated previously to be direct-acting vasodilators. See U.S. Pat. No. 4,057,636 and Petersen, J. Med. Chem., 21(8), 773 (1982). The cyanoguanidine unit was explored as a bioisosteric replacement for the potentially toxic thiourea moiety, and this resulted in an increase in vasodilator potency. A variety of alkyl groups provided antihypertensive activity, with the best compounds possessing branching at the carbon alpha to the nitrogen. Both 4- and 3-pyridyl isomers were potent vasodilators. The 2-pyridyl isomers were essentially inactive. In Peterson, J. Med. Chem., 21(8), 773 (1982), pinacidil is compound number 50 and the 3-pyridyl isomer is compound number 17. In this report, the minimal effective dose (MED) of pinacidil to decrease blood pressure in spontaneously hypertensive rats was 0.5 mg/kg whereas the MED of the 3-pyridyl isomer was 1 mg/kg.
Pinacidil is currently undergoing clinical trials to determine its antihypertensive potential. By virtue of the branched N-alkyl side chain, pinacidil is a mixture of two enantiomers. Recently, both enantiomers have been prepared and studied -- see, Weston et al., Drugs, 36 (Suppl. 7), 10 (1988). It was reported that the (-) isomer of pinacidil was more potent than the (+) isomer.
We have now discovered that the (-) isomer of the 3-pyridyl isomer of pinacidil is considerably more potent as a potassium channel opener as compared with its (+) enantiomer, pinacidil, or any of the pinacidil enantiomers.